A CoQ10 analog ameliorates cognitive impairment and early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation.

Subarachnoid hemorrhage (SAH) represents a stroke subtype that can lead to prolonged cognitive deficits as well as death or disability. Prior investigation has suggested that CoQ10 analogs can mitigate oxidative stress and inflammation and promote mitochondrial biogenesis in the context of brain injury and neurodegenerative disorders. However, the precise mechanisms underlying early brain injury (EBI) following SAH remain incompletely understood, and the detailed molecular processes have yet to be completely clarified. This investigation examined the neuroprotective properties of a CoQ10 analog concerning EBI post-SAH and identified potential mechanistic pathways. Our findings indicate that SAH led to alterations in innate and learned behaviors in aged C57BL/6J mice while also triggering ferroptosis and neuroinflammation within hippocampal neurons. Additionally, SAH was associated with reduced ferroptosis-related proteins, exacerbation of iron accumulation, elevation of lipid ROS, and decreased FSP1, HO-1, and NQO1 levels. The CoQ10 analog idebenone (IDB) demonstrated a capacity to alleviate EBI, as evidenced by improvements in both innate and learned behaviors, alongside a reduction in ferroptosis-related gene/protein expression. Silencing of FSP1 exacerbated EBI, ferroptosis, and neuroinflammation, and partially counteracted the neuroprotective effects of the CoQ10 analog. These results suggest that IDB may enhance the recovery from SAH-induced EBI in aged mice by modulating FSP1 protein stability via NMT-mediated N-myristoylation, thereby inhibiting both ferroptosis and neuroinflammation. The potential therapeutic application of IDB as a clinical intervention for EBI following SAH is also highlighted.